PROJECT 3 - Molecular mechanisms of gene x stress effects on pre-disease endophenotypes PROJECT SUMMARY In our prior collaborative work, using a focused genetic approach in well-phenotyped human cohorts, we have identified consistent associations between variants in candidate genes, ?endophenotypes?, and disease endpoints. However, the pathways and mechanisms mediating our other identified genetic associations are poorly understood. Evolving molecular technologies now enable rapid, high-throughput profiling of millions of circulating genetic and other ?omic? markers; using sophisticated analytic and bioinformatics techniques, these ?omic? profiles can be integrated to understand biological pathways underlying disease traits, focused genetic associations, response to medications/environment, etc. Thus, in this proposal, we will integrate genetics, metabolomics, transcriptomics, and epigenetics profiled in blood samples from several large, well-phenotyped cohorts to identify novel biomarkers and molecular pathways mediating these relationships. We will also use this approach in a hypothesis generating approach for unique phenotypes that link psychosocial stress with CVD (i.e. Takosubo?s cardiomyopathy and mental stress induced ischemia). We will accomplish our goals for this Project through the following Specific Aims: (1) to test the hypothesis that epigenetic variation in candidate genes from our prior work, will also be associated with the same endophenotypes and disease endpoints, and incrementally influence expression of the gene on those phenotypes; (2) to integrate epigenetics, transcriptomics and metabolomics in an ?unbiased? systems biology approach, with the goal of elucidating mechanisms mediating the associations between SNPs, endophenotypes and CVD endpoints from our prior work; (3) to identify genetic and epigenetic variants associated with novel phenotypes linking psychosocial stress with CVD.